Oxygen-Delivering Semiconducting Polymer Nanocytokines for Sono-Induced Combination Immunotherapy of Orthotopic Pancreatic Cancer

Due to the hypoxic and immunosuppressive tumor microenvironment, pancreatic cancer is poorly responsive to immunotherapy. Cytokines offer a good occasion to reinforce immune responses via overcoming immunotherapy resistance, but their short half-life and unbridled biodistribution often limit their therapeutic effects and cause off-tumor adverse effects. In this study, an oxygen-delivering semiconducting polymer nanocytokine is designed for sono-induced combination immunotherapy of orthotopic pancreatic cancer. Such a nanocytokine (SPNI) is constructed based on the sonodynamic semiconducting polymer as a skeleton, which is loaded with an oxygen carrier, perfluorohexane (PFH), and conjugation of interleukin-12 (IL-12) via a singlet oxygen (¹O₂)-cuttable thioketal (TK) fragment. Via enriching into orthotopic pancreatic tumor sites, SPNI delivers oxygen to relieve tumor hypoxia, which greatly amplifies the sonodynamic therapy (SDT) efficacy with ultrasound treatment, and also immunogenic cell death is triggered. More importantly, SPNI precisely delivers IL-12 into orthotopic pancreatic tumor sites via the severing of the TK fragments by the generated ¹O₂, resulting in the activation of strong antitumor immune responses. Such a sono-induced combination immunotherapy of SPNI exhibits an amplified efficacy in eradicating orthotopic pancreatic cancer and inhibiting tumor metastasis, thus offering a promising program for cancer therapy.